Marijuana has long been known to increase appetite, and the selective cannabinoid CB1 receptor antagonist SR141716A has been recently reported to decrease food intake in rodents. We took advantage of mice deficient in CB1 receptors (CB1-/- mice) and their wild-type controls (CB1+/+ mice) to examine the possible involvement of endogenous cannabinoids in the physiologial regulation of food intake. In animals with unrestricted access to food, food intake was similar in CB1-/- and CB1+/+ mice. Brief food deprivation increased food intake significantly more in CB1+/+ than in CB1-/-mice, and pretreatment of such mice with SR141716A reduced food intake in wild-type but not in Cb1-/- mice. These findings indicate a role of endocannabinoids acting at CB1 receptors in the hunger-induced increase in food intake. Adipocyte-derived leptin is the primary signal through which the brain senses nutritional status. Leptin regulates energy expenditure and food intake by upregulating anorexigenic hormones, such as a-MSH, and downregulating orexigenic hormones, such as NPY, in the hypothalamus. Acute treatment of rats with leptin reduced hypothalamic, but not cerebellar, levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), whereas hypothalamic AEA and 2-AG were increased in genetically obese animals with defective leptin signaling. Furthermore, chronic treatment of obese db/db mice with SR141716A reduced food intake as well as weight gain. These findings indicate that hypothalamic endocannabinoids are under the negative regulatory influence of leptin, and they may contribute to the hyperphagia and obesity in animals with defective leptin signaling.